Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease ranging from simple fatty liver (steatosis), to nonalcoholic steatohepatitis (NASH), to cirrhosis (irreversible, advanced scarring of the liver). All of the stages of NAFLD have in common the accumulation of fat (fatty infiltration) in the liver cells (hepatocytes). In NASH, the fat accumulation is associated with varying degrees of inflammation (hepatitis) and scarring (fibrosis) of the liver.
The term nonalcoholic is used because NAFLD and NASH occur in individuals who do not consume excessive amounts of alcohol. Yet, in many respects, the histological picture of NAFLD is similar to what can be seen in liver disease that is due to excessive intake of alcohol.
The NAFLD spectrum is thought to begin with and progress from its simplest stage, called simple fatty liver (steatosis). That is, fatty liver is the initial abnormality in the spectrum of NAFLD. Simple fatty liver involves just the accumulation of fat in the liver cells with no inflammation or scarring. The fat is actually composed of a particular type of fat (triglyceride) that accumulates within the liver cells. Fatty liver is a harmless (benign) condition.
The next stage and degree of severity in the NAFLD spectrum is NASH. As mentioned, NASH involves the accumulation of fat in the liver cells as well as inflammation of the liver. The inflammatory cells can destroy the liver cells (hepatocellular necrosis). In the terms “steatohepatitis” and “steatonecrosis”, steato refers to fatty infiltration, hepatitis refers to inflammation in the liver, and necrosis refers to destroyed liver cells. Strong evidence suggests that NASH, in contrast to simple fatty liver, is not a harmless condition. This means that NASH can ultimately lead to scarring of the liver (fibrosis) and then irreversible, advanced scarring (cirrhosis). Cirrhosis that is caused by NASH is the last and most severe stage in the NAFLD spectrum.
There are many other causes of fat accumulation in the liver besides NAFLD. However, NAFLD and NASH are considered the primary fatty liver diseases. The secondary fatty liver diseases include those that occur in other types of liver disease. Thus, alcoholic liver disease (ALD), discussed below, is the most frequent secondary fatty liver disease. Secondary fatty liver can also occur in chronic viral hepatitis C (HCV), chronic viral hepatitis B (HBV), chronic autoimmune hepatitis (AIH), diabetes and Wilson's disease. (In AIH, the body's immune defense system mistakenly attacks its own liver. In Wilson's disease, an accumulation of copper injures the liver.) In all of these secondary fatty liver diseases, fatty liver is associated with other liver abnormalities distinct from NAFLD and is thought to result from liver cell injury.
Another type of secondary fatty liver disease is unrelated to other specific liver diseases. In these cases, the accumulation of liver fat is due to disturbances in the body's processing (metabolism) of fat (lipid) rather than to direct injury to the liver cells. Such causes include certain drugs (e.g., prednisone), some gastrointestinal disorders such as Intestinal Bacterial Overgrowth (IBO), gastroparesis and irritable bowel (IBS) disorders, patients exposed to chemotherapy in cancer treatments, gastrointestinal operations (bariatric surgery) for obesity, malnutrition, and genetic defects in proteins that process (metabolize) lipids.
The major causes of fatty liver include: (1) protein malnutrition; (2) diabetes mellitus; (3) obesity; (4) corticosteroid treatment; (5) jejunoileal bypass; (6) chronic illnesses associated with impaired nutrition or malabsorption; (7) total parental nutrition (TPN or intravenous hyperalimentation); and (8) pregnancy. (Isselbacher, K. J. and D. K. Podosky, Infiltrative and Metabolic Diseased affecting the Liver in Harrison's Principles of Internal Medicine Eds. Brawnwald, E. et al pp. 1353-54, 1988). Although these causes appear disparate, it has been hypothesized that the accumulation of fat in the liver can be attributed to a perturbation of one of the following steps in the lipid metabolism of hepatocytes and adipocytes: (1) increase free fatty acid delivery to the liver; (2) increased free fatty acid synthesis within the liver; (3) decreased beta-oxidation of fatty acids; and (4) decreased very low-density lipoprotein synthesis or secretion. (Bacon, B. R. et al, Nonalcoholic Steatohepatitis: An Expanded Clinical Entity, Gastroenterology, 107:1103-1109, 1994).
The clinical profile found in patients with fatty liver tend to be similar, but the best descriptions are those associated with alcohol ingestion, thus the name “alcoholic hepatitis.” See Achord, J. L., Review of Alcoholic Hepatitis and Its Treatment, The American Journal of Gastroenterology, 88(11):1822-1828, 1993. Alcoholic hepatitis, also referred to as “florid cirrhosis,” “toxic hepatitis” and “acute alcoholic hepatitis,” is not a syndrome separate from alcoholic fatty liver. Necrosis is merely another manifestation of hepatic injury related to alcohol. Although on a liver biopsy, much fat can be observed, fat may also be almost totally absent. In addition, liver biopsy may be marked by cell necrosis, polymorphonuclear inflammatory infiltrate of variable intensity and fatty metamorphosis. All of the acute changes induced by alcohol (e.g., fatty liver, alcoholic hepatitis and acute fatty liver with cholestasis) are potentially reversible. The diagnosis can be suspected clinically, but differential diagnosis is best made by needle biopsy of the liver.
The syndrome of encephalopathy and fatty liver was first defined by Reye in 1963 (see Reye, et al, Encephalopathy and fatty degeneration of the viscera. Lancet, 2:749 (1963); Schubert et al, Encephalopathy and Fatty Liver (Reye's Syndrome), in: Popper, H. and Schaffner, F. (eds.): Progress in Liver Diseases. Chap. 28, 4th Edition, New York, Grune and Stratton, Inc., 1972, pp. 489-510). The causes are unknown and may be multiple. Even with today's technological advances, the mortality rate is still very high at 38%.
In view of the above discussion of the enormity of the different fatty liver diseases and disorders, an inexpensive, easy to administer, physically tolerable and effective treatment for this group of diseases is clearly needed.